Endometriosis is a common estrogen-dependent gynecological disease, which often occurs in women of childbearing-age, though the mechanism is unclear. The difficult diagnosis and unclear pathogenesis of endometriosis severely hinder the discovery of effective treatments. At present, endometriosis is mainly diagnosed by laparoscopy, and treated by surgery, or controlled by taking contraceptives, GnRH receptor agonists, or progestogen to reduce body estrogen levels.
Presently, the incidence rate of endometriosis is high. Statistical data from Datamonitor 2009 shows that the number of female patients suffering from endometriosis has been more than 68 million in only two countries (India and China) (31,288,000 in India, 37,535,000 in China), while the data in the seven major markets has been more than 17 million. Datamonitor expects that during 2009-2018, the endometriosis drug market will grow from $764 million in 2009 ($596 million in US, $117 million in European Union, $51 million in Japan) to $1.156 billion in 2018 ($844 million in US, $206 million in European Union, $106 million in Japan), and the growing space in the Chinese market will be larger.
Gonadotropin-releasing hormone (Gonadoliberin; GnRH), also known as luteinizing hormone releasing hormone (LHRH), is a decapeptide hormone (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) synthesized by hypothalamic neuroendocrine cells, and is a central regulatory factor of the endocrine reproductive system. GnRH plays an important role in the hypothalamus-pituitary-gonadal axis system by being transported to the pituitary through the hypothalamic pituitary portal circulation system and then binding to GnRH receptor cells in the anterior pituitary, by promoting the secretion and release of gonadotropin luteinizing hormones, slier as Luteinizing Hormone (LH) and follicle-stimulating hormone (FSH), and by regulating normal development of the ovary and corpus luteum. GnRH receptor plays its regulatory role by coupling with G protein, which is capable of activating the calcium phosphatidylinositol second messenger system. LH regulates the production of sex steroids, and FSH regulates male spermatogenesis and maturation of female ovarian follicles.
LH and FSH are released into circulation, and bind to receptors on the specific cells of ovaries or testes to stimulate steroid production. Diseases such as endometriosis, uterine leiomyoma, and prostate cancer are aggravated in the presence of sex steroids. It is necessary to administer long-acting peptide GnRH receptor agonists and antagonists to control the diseases.
Peptide GnRH receptor antagonists include GnRH-derived linear peptides (U.S. Pat. No. 5,171,835), cyclic hexapeptide derivatives (U.S. Pat. No. 2002/0065309), bicyclic peptide derivatives (Journal of Medicinal Chemistry, 1993; 36: 3265-73), etc.; and peptide GnRH receptor agonists include Leuprorelin (pGlu-His-Trp-Ser-Tyr-d-Leu-Leu-Arg-Pro-NHEt). However, there are many unresolved issues for peptide compounds including oral absorption, dosage form, dose volume, drug stability, sustained action, and metabolic stability and the like. The primary reason that small molecule GnRH receptor antagonist therapy is superior to the existing peptide-based therapy is largely due to the oral administration of small molecule GnRH receptor antagonists, which is convenient and efficient. Studies have shown that small molecule antagonists have a significant efficacy for hormone-dependent diseases such as endometriosis, precocious puberty, and prostate cancer.
An indirect tumor inhibition mechanism mediated by GnRH agonists is that GnRH agonists decrease the secretion of sex hormones and then indirectly inhibit the growth of tumor cells by long-term effects on the hypothalamic-pituitary-gonadal axis, which leads to a reduction of pituitary gonadotropins (FSH, LH), whereas GnRH receptor antagonists directly inhibit the release of pituitary gonadotropins, and then inhibit the growth of tumor cells.
In view of the limitations of peptide GnRH receptor antagonists, certain non-peptide GnRH receptor antagonists have been proposed and put into development, clinical trials, and marketing stages. For example, Elagolix (also known as NBI-56418 or ABT-620), is a small molecule GnRH receptor antagonist co-developed by Abbott and Neurocrine Biosciences Inc, which is currently in phase III clinical stage, and mainly used for the treatment of endometriosis (phase III) and uterine leiomyoma (phase II). In June 2012, the data from the endometriosis phase II trial were presented at the 94th Annual Meeting of the Endocrine Society in Houston. Among the 131 women suffering from endometriosis who were treated with elagolix (150 or 250 mg qd), leuprorelin depot (3.75 mg sc, once a month for 12 weeks) or placebo, the serum estrogen level in the patients of the elagolix treatment group was lower than that of the leuprorelin treatment group and placebo group. Meanwhile, the safety and tolerability of elagolix has been well verified.
Relugolix, also known as TAK-385, is an oral small molecule GnRH receptor antagonist developed by Takeda Pharmaceutical in Japan, which is used for the treatment of endometriosis, uterine leiomyoma, and prostate cancer. The study of endometriosis and uterine leiomyoma has been in phase II clinical trials since 2011, and the study of prostate cancer has been in phase I clinical trials since the same year.
At present, a series of patent applications concerning small molecule GnRH receptor antagonists have been published, including WO2006096785, WO2010026993, WO2011076687, WO2012175514, etc.
Despite numerous significant studies that have been conducted in this field, there remains a need to develop more effective small molecule GnRH receptor antagonists. The present disclosure provides structurally new GnRH receptor antagonists, and it is found that compounds having such structures have good activity, and exhibit excellent treatment effects for endocrine reproductive system diseases.